title: The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expression.
abstract: Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17∼92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17∼92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17∼92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17∼92-deficient TFH cells. Our results identify the miR-17∼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program.
authors.affiliation: Department of Microbiology & Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Baumjohann
authors.forename: Robin
authors.initials: R
authors.lastname: Kageyama
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Clingan
authors.forename: Malika M
authors.initials: MM
authors.lastname: Morar
authors.forename: Sana
authors.initials: S
authors.lastname: Patel
authors.forename: Dimitri
authors.initials: D
authors.lastname: de Kouchkovsky
authors.forename: Oliver
authors.initials: O
authors.lastname: Bannard
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Matloubian
authors.forename: K Mark
authors.initials: KM
authors.lastname: Ansel
authors.forename: Lukas T
authors.identifier: 0000000233598796
authors.initials: LT
authors.lastname: Jeker
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000276:immunology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000276:immunology*; D018709:Statistics, Nonparametric; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*
chemical_list: C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539739:Rora protein, mouse